There is a point with acute liver injuries when immediate action or inaction can drastically affect patient outcomes with very little middle ground. Action could save someone’s life, while inaction could be fatal.
“You suddenly arrive at a fork in the road where if you can influence the patient’s liver to go down the good path, they can recover,” said Dr. Norman L. Sussman, chief medical officer at Durect Corp. “There’s this moment of intervention where you say, if I knew what to do at this particular moment, I could change the course of this patient’s disease.”
Acetaminophen overdose is one of the most common causes of acute liver failure that can lead patients to this fork in the road. If it’s treated correctly, the patient nearly always survives, but if you miss the opportunity, they could die.
That aspect of hepatology has always fascinated Sussman and informed his career as a hepatologist, including his work today at the clinical-stage biotech company Durect, which is using its endogenous epigenetic regulator program to develop treatments for acute organ injury and chronic liver diseases.
In October, Durect announced it had reached an enrollment milestone for a phase 2b trial of its lead product candidate, larsucosterol, which the company hopes will be the first approved treatment for severe alcohol-associated hepatitis (AH).
Arriving at life-changing forks in the road has seemed to define many parts of Sussman’s life. There have been the treatment pivot points that doctors encounter with patients. But he also encountered a fork in the road when he made the decision to leave apartheid South Africa in the late 1970s and reject the status quo of racial segregation that so many people were content to accept.
He arrived at another in late 2020, when he was on the brink of retirement from the Baylor College of Medicine, where he was an associate professor and director of Project ECHO at Baylor St. Luke's Medical Center. Instead of taking the time to consider his next move like he’d originally planned, he decided to accept the role of chief medical officer at Durect because he was so intrigued by the science.
“Sometimes in life you get an opportunity when you say, this is so important and so big and so close to what I’m interested in, that you would be foolish to walk away from it,” he said.
A ‘game changer’
Forks in the road can also result in treatment possibilities for patients, and that’s what Sussman saw when he attended the 2019 meeting of the American Association for the Study of Liver Diseases, where Durect presented mid-stage data. The results showed that AH patients treated with larsucosterol had a 100% survival rate during the 28-day follow-up period, compared to a historical 26% mortality rate.
“I thought, this is one of the most exciting things I’ve seen in this field in a long time,” he said. “I can define certain events where I say, ‘This was a game changer,’ and that’s what I felt about this.”
"Sometimes in life you get an opportunity when you say, this is so important and so big and so close to what I’m interested in, that you would be foolish to walk away from it."
Sussman spent his career in hepatology frustrated by AH. Hepatitis is inflammation of the liver with varying causes and a potential cure, but AH isn’t currently curable or even easily treatable. Quitting drinking is recommended as a first course of action, but it isn’t always enough to reverse severe damage. Although current steroidal treatments reduce inflammation, they don’t improve long-term survival.
“People have used a variety of things to downregulate inflammation, but they haven’t been terribly effective,” Sussman said.
Durect’s candidate takes a different approach. DNA hypermethylation is an irregularity found in patients with severe AH. Larsucosterol regulates patterns of gene expression without modifying the DNA sequence and inhibits DNA methylation, which could improve cell survival, reduce inflammation and decrease lipotoxicity.
That constellation of effects is important because of the nature of AH as a disease. Some diseases are caused by a single gene that’s not functioning, but others, like AH, are more complex.
“When you have a complex disease like AH, dealing with just one aspect of the disease may not be as effective,” Sussman said. While steroids might address one part of AH — inflammation — that “doesn’t seem to be enough to change the course of severe AH.”
Larsucosterol has that potential, Sussman said. It could also be used to treat acute organ injury and other chronic diseases where DNA hypermethylation plays a role.
“Honestly, I never thought I’d see anything like that. It was so incredible,” he said of the biochemistry results he saw at the AASLD meeting. “I could not believe how good that result was.”
Now the company is enrolling patients at more than 60 clinical trial sites across the U.S., U.K., Europe and Australia, and expects to read out topline results in the second half of 2023.
Making big choices
Sussman was born and raised in South Africa during apartheid. As a white person, he was part of that country’s privileged class and went to medical school at the University of the Witwatersrand. It would have been very easy for him to do what many white South Africans did at the time: enjoy their status and live their lives comfortably.
“People are very capable of ignoring big problems,” he said. “There are people who said, ‘That’s just the way it is. I’m fortunate to be white, and I’m living in a place where life is easy.’”
But Sussman and his wife decided they would not be among those people, and they left, first going to the U.K. and then to the U.S.
“My wife and I were very unhappy with (apartheid) as a backdrop, and honestly I didn’t imagine that it would ever resolve peacefully,” he said.
Now, fairness and equality enter into his work as a hepatologist and Durect’s goal to develop a treatment for AH. Sussman doesn’t believe that the stigma of alcoholism should play any part in treatment.
“So if someone has a drinking problem … they have an issue that I would like to help them with,” he said. “Can I use my skills to make this person’s life better? Doing that one at a time is very satisfying as a physician. But being able to affect the lives of thousands or hundreds of thousands of people by developing a product that is useful is 100,000 times better.”